A Bayesian order-restricted model for hormonal dynamics during menstrual cycles of healthy women.

We propose a Bayesian framework for analyzing multivariate linear mixed effect models with linear constraints on the fixed effect parameters. The procedure can incorporate both firm and soft restrictions on the parameters and Bayesian model selection for the random effects. The framework is used to analyze data from the BioCycle study. One of the main objectives of the BioCycle study is to investigate the association between markers of oxidative stress and hormone levels during menstrual cycles of healthy women. Contrary to the popular belief that ovarian hormones are negatively associated with level of F (2) -isoprostanes, a known marker for oxidative stress, our analysis finds a positive association between ovarian hormone levels and isoprostane levels. The positive association corroborates the findings from a previous analysis of the BioCycle data.

The fatty acid oxidation product 15-A3t-isoprostane is a potent inhibitor of NFκB transcription and macrophage transformation.

Fatty acids such as eicosapentaenoic acid (EPA) have been shown to be beneficial for neurological function and human health. It is widely thought that oxidation products of EPA are responsible for biological activity, although the specific EPA peroxidation product(s) which exert these responses have not yet been identified. In this work we provide the first evidence that the synthesized representative cyclopentenone IsoP, 15-A(3t)-IsoP, serves as a potent inhibitor of lipopolysaccharide-stimulated macrophage activation. The anti-inflammatory activities of 15-A(3t)-IsoP were observed in response not only to lipopolysaccharide, but also to tumor necrosis factor alpha and IL-1b stimulation. Subsequently, this response blocked the ability of these compounds to stimulate nuclear factor kappa b (NFκB) activation and production of proinflammatory cytokines. The bioactivity of 15-A(3t)-IsoP was shown to be dependent upon an unsaturated carbonyl residue which transiently adducts to free thiols. Site directed mutagenesis of the redox sensitive C179 site of the Ikappa kinase beta subunit, blocked the biological activity of 15-A(3t)-IsoP and NFκB activation. The vasoprotective potential of 15-A(3t)-IsoP was underscored by the ability of this compound to block oxidized lipid accumulation, a critical step in foam cell transformation and atherosclerotic plaque formation. Taken together, these are the first data identifying the biological activity of a specific product of EPA peroxidation, which is formed in abundance in vivo. The clear mechanism linking 15-A(3t)-IsoP to redox control of NFκB transcription, and the compound's ability to block foam cell transformation suggest that 15-A(3t)-IsoP provides a unique and potent tool to provide vaso- and cytoprotection under conditions of oxidative stress.

Isoprostanes and asthma.

Isoprostanes are prostaglandin (PG)-like compounds generated in vivo following oxidative stress by non-enzymatic peroxidation of polyunsaturated fatty acids, including arachidonic acid. They are named based on their prostane ring structure and by the localization of hydroxyl groups on the carbon side chain; these structural differences result in a broad array of isoprostane molecules with varying biological properties. Generation of specific isoprostanes is also regulated by host cell redox conditions; reducing conditions favor F2-isoprostane production while under conditions with deficient antioxidant capacity, D2- and E2-isoprostanes are formed. F2-isoprostanes (F2-isoP) are considered reliable markers of oxidative stress in pulmonary diseases including asthma. Importantly, F2-isoP and other isoprostanes function as ligands for PG receptors, and potentially other receptors that have not yet been identified. They have been reported to have important biological properties in many organs. In the lung, isoprostanes regulate cellular processes affecting airway smooth muscle tone, neural secretion, epithelial ion flux, endothelial cell adhesion and permeability, and macrophage adhesion and function. In this review, we will summarize the evidence that F2-isoP functions as a marker of oxidative stress in asthma, and that F2-isoP and other isoprostanes exert biological effects that contribute to the pathogenesis of asthma. This article is part of a Special Issue entitled Biochemistry of Asthma.